Many steroid compounds have been used as topical therapeutic agents for eye inflammations. While those steroid compounds show a potent antiinflammatory action, they tend to cause secondary (iatrogenic) disorders of the eye, such as cataract and glaucoma.
Therefore, research has been done to develop steroid compounds which do not cause adverse reactions even when administered topically to the eye and recently loteprednol etabonate (hereinafter sometimes referred to briefly as LE) having very satisfactory antiinflammatory activity and only a low risk for side effects has been developed by modification of prednisolone acetate (U.S. Pat. Nos. 4,716,495 and 4,996,335).
LE is devoid of the 20-keto group in the 17.beta.-position of prednisolone and instead has in this 17.beta.-position an ester residue which is hydrolyzed in vivo to give an inert carboxylic acid metabolite which does not bind to the glucocorticoid receptor. Therefore, unlike many other steroidal agents, LE has a low incidence of side effects such as onset of cataract and elevation of intraocular pressure, thus being a very useful compound for the treatment of ocular inflammations.
Since LE is a substantially water-insoluble crystalline substance, its dosage form has to be an aqueous suspension in order that it may be used as eye drops or nasal drops. However, when LE is formulated with an isotonizing agent such as sodium chloride and a buffer such as phosphoric acid, both of which are conventionally added in the preparation of an aqueous suspension, particles of LE begin to aggregate within 3 months and, in certain cases, within a month.
To overcome this disadvantage, there was proposed an aqueous suspension of LE formulated with a nonionic suspending agent such as polyvinylpyrrolidone (PVP), polyvinyl alcohol (PVA), etc., a nonionic surfactant such as tyloxapol, polysorbate 80, etc., and further an isotonizing agent of polyhydric alcohols such as glycerin and mannitol (PCT/US94-12059) with fairly successful results. However, this formulation makes it difficult to control pH in the preparation of the aqueous suspension and, moreover, when the suspension is stored for a long time, there occurs a pH depression despite little change in appearance so that it elicits an irritable response in the eye or nasal mucosa.